Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial

Background and Purpose: Randomized patent foramen ovale closure trials have used open-label end point ascertainment which increases the risk of bias and undermines confidence in the conclusions. The Gore REDUCE trial prospectively performed baseline and follow-up magnetic resonance imaging (MRIs) for all subjects providing an objective measure of the effectiveness of closure. Methods: We performed blinded evaluations of the presence, location, and volume of new infarct on diffusion-weighted imaging of recurrent clinical stroke or new infarct (>3 mm) on T2/fluid attenuated inversion recovery from baseline to follow-up MRI at 2 years, comparing closure to medical therapy alone. We also examined the effect of shunt size and the development of atrial fibrillation on infarct burden at follow-up. Results: At follow-up, new clinical stroke or silent MRI infarct occurred in 18/383 (4.7%) patients who underwent closure and 19/177 (10.7%) medication-only patients (relative risk, 0.44 [95% CI, 0.24–0.81], P =0.02). Clinical strokes were less common in closure patients compared with medically treated patients, 5 (1.3%) versus 12 (6.8%), P =0.001, while silent MRI infarcts were similar, 13 (3.4%) versus 7 (4.0%), P =0.81. There were no differences in number, volumes, and distribution of new infarct comparing closure patients to those treated with medication alone. There were also no differences of number, volumes, and distribution comparing silent infarcts to clinical strokes. Infarct burden was also similar for patients who developed atrial fibrillation and for those with large shunts. Conclusions: The REDUCE trial demonstrates that patent foramen ovale closure prevents recurrent brain infarction based on the objective outcome of new infarcts on MRI. Only clinical strokes were reduced by closure while silent infarctions were similar between study arms, and there were no differences in infarct volume or location comparing silent infarcts to clinical strokes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00738894.

Silent myelin-weighted magnetic resonance imaging

Background: Inhomogeneous Magnetization Transfer (ihMT) is an emerging, uniquely myelin-specific magnetic resonance imaging (MRI) contrast. Current ihMT acquisitions utilise fast Gradient Echo sequences which are among the most acoustically noisy MRI sequences, reducing patient comfort during acquisition. We sought to address this by modifying a near silent MRI sequence to include ihMT contrast. Methods: A Magnetization Transfer preparation module was incorporated into a radial Zero Echo-Time sequence. Repeatability of the ihMT ratio and inverse ihMT ratio were assessed in a cohort of healthy subjects. We also investigated how head orientation affects ihMT across subjects, as a previous study in a single subject suggests this as a potential confound. Results: We demonstrated that ihMT ratios comparable to existing, acoustically loud, implementations could be obtained with the silent sequence. We observed a small but significant effect of head orientation on inverse ihMTR. Conclusions: Silent ihMT imaging is a comparable alternative to conventional, noisy, alternatives. For all future ihMT studies we recommend careful positioning of the subject within the scanner.

Silent myelin-weighted magnetic resonance imaging

Background: Inhomogeneous Magnetization Transfer (ihMT) is an emerging, uniquely myelin-specific magnetic resonance imaging (MRI) contrast. Current ihMT acquisitions utilise fast Gradient Echo sequences which are among the most acoustically noisy MRI sequences, reducing patient comfort during acquisition. We sought to address this by modifying a near silent MRI sequence to include ihMT contrast. Methods: A Magnetization Transfer preparation module was incorporated into a radial Zero Echo-Time sequence. Repeatability of the ihMT ratio and inverse ihMT ratio were assessed in a cohort of healthy subjects. We also investigated how head orientation affects ihMT across subjects, as a previous study in a single subject suggests this as a potential confound. Results: We demonstrated that ihMT ratios comparable to existing, acoustically loud, implementations could be obtained with the silent sequence. We observed that the ihMT ratio varied with the orientation of the head. Conclusions: Silent ihMT imaging is a comparable alternative to conventional, noisy, alternatives. For all future ihMT studies we recommend careful attention should be paid to subject positioning within the scanner.

Abstract WMP110: Presence, Volume, and Location of New Ischemic Injury on MRI in Stroke Patients Who Undergo PFO Closure Compared to Patients Treated Medically: An Analysis of the REDUCE Trial

Background: Randomized PFO closure trials have used open-label endpoint ascertainment, which may increase the risk of bias and undermine confidence in the conclusions. The Gore REDUCE Trial prospectively performed baseline and follow-up MRIs for all subjects, thereby providing an objective measure of the effectiveness of closure. Methods: The presence, location, and volume of new infarct, defined as an acute DWI lesion at time of recurrent clinical stroke or new lesion (>3mm) on T2/FLAIR from baseline to follow up MRI at 2 years, was evaluated using a semi-automated methodology blinded to treatment assignment, comparing patients randomized to undergo closure to those assigned medical therapy. Results: There were no differences in total new infarct volume, new large infarct (>3cm diameter), or new infarct location, comparing patients who underwent closure to those treated with medication (Table). New clinical stroke or clinically silent MRI infarct occurred in 18/383 (4.7%) patients who underwent closure and 19/177 (10.7%) of medically treated patients, RR 0.44, 95% CI 0.24-0.82, p=0.008. Recurrent clinical ischemic stroke occurred in 5/383 (1.3%) vs 12/177 (6.8%), RR 0.19, 95% CI 0.07-0.54, p=0.005, and silent brain infarction in 13/383 (3.3%) vs 7/177 (4.0%), RR 0.86, 95% CI 0.34-2.11, p=0.74. Conclusions: New MRI infarcts were generally small and the volumes and distribution of injury were similar between patients randomized to closure and those assigned to aspirin alone. The finding that silent infarcts were not smaller in volume than clinical ischemic strokes and that only clinical strokes were reduced by closure suggests that there may be ascertainment bias in clinical outcomes during open label studies. Nevertheless, as MRI is an objective outcome assessed blinded to randomization assignment, the REDUCE trial provides the highest level of evidence that PFO closure prevents recurrent ischemic brain injury, reducing new infarcts by more than half.

Silent Brain MRI Infarcts and Subsequent Stroke Type In the Cardiovascular health Study

P136 Objective: Silent infarcts seen on cranial MRI scans are a risk factor for subsequent clinical stroke in the elderly. This study examines the type of clinical strokes seen in those with silent infarcts. Methods: Cranial MRI examination was completed on 3324 Cardiovascular Health Study (CHS) participants aged 65+ who were without a prior history of clinical stroke. Incident strokes were identified over an average follow-up of 4 years and classified as hemorrhagic or ischemic. Ischemic strokes were further subdivided into lacunar, cardioembolic, atherosclerotic or other/unknown. Results: Silent MRI infarcts >3mm were found in approximately 28% (n=923). Of these, 7% (n=67) subsequently had a clinically evident stroke. The characteristics of the silent MRI infarcts in those who sustained an incident stroke were as folows: 56 had only subcortical infarcts, of which 55 were <20mm; 4 had only cortical infarcts; and 7 had both cortical and subcortical infarcts. Of those with only subcortical silent MRI infarcts, 16% (n=9) went on to a hemorrhagic stroke and 84% (n=47) sustained an ischemic stroke. The ischemic strokes were subtyped as 12 cardioembolic, 3 lacunar, 2 atherosclerotic and 30 unknown/other. Considering only those with cortical silent infarcts, either alone or in combination with subcortical infarcts, there was 1 hemorrhagic stroke and 10 ischemic strokes. Half of the ischemic strokes were cardioembolic and half were unknown type. Conclusion: Elderly individuals with silent subcortical infarcts who go onto subsequent stroke may be at risk not only for lacunar infarcts but also cardioembolic or hemorrhagic strokes.